Renal Medullary Amyloidosis

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    Ve t .Pathol .26:129-135(1989)

    RenalMedullaryAmyloidosisinDorcasGazellesB.A.RiDEOUT,R.J.MoNTALi,R.S.WALLACE,M.USH,L.G.PHILLIPS,JR.,T.T.ANTONOVYCH,ANDS.G.ABNIS

    DepartmentsofPa t ho logyandAnimalHea l t h ,NationalZoologicalPark,SmithsonianInstitution,Washington,DC;andDivision ofNephropathology, ArmedForcesInstituteofPathology,Washington,DC Abstract .e tweenJanuary97 6andSep t ember987rena lmedullaryamyloidosis(RMA)w asdiagnosed in7Dorcasgazelles;th enecropsypreva lencerate was7/32(53%).Th emostsevere amyloiddepositswere inth erena lmedulla ;glomeruliwerespared.Rena lcorticallesionsofintersti t ialfibrosisa nd tubularatrophy

    anddilatationignificantlycorre la tedwithRM AP

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    1 3 0 Rideoute tal .

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    Fig.3.enalmedulla.Amyloidencroachesonmedullary tubulesand collectingducts.Atrophyand losso f manytubules.Onetubule(rightcenter)hasregeneratingepithelium.HE.Fig.4.enalmedulla,medullaryamyloidosis.Tubularbasementmembranes(arrows)are thickenedan dinfiltratedbyamyloidfibrils.Inset:amyloidfibrils.t ion.One gazel le ( 84 - 386 )also hadprominentamyloiddepositionnh ewallsofmedium-andarge-sized arteriesthroughoutth ekidney.Anotheranimal( 81 -6 2 3 )hadmoderateperitubulardepositsin th e cortex,buta llo the rshadminimalornocorticalinterstitialamyloid.Theglomerul iweresparedinallcases.Althoughth e tipoftherenalpapillawaspresentin onlysevenof thekidneysections,coagulative necrosisofthepapillaw asidentifiedinthreegazel les .Inone ,th e necrosiswasextensive butlimitedto th e tip of th e papil la .Theother tw o hadpa tchy necrosisthroughoutthemedul la ,withextensive mineralizationofth ene -crotic reasn ne .Mineralizationofmedul la rytu-bulesandnterstitiumwasnotedn necasewhich l ackedevidence ofpapillarynecrosis.Cort ica lchangesincludedvariabledegreesoftubularatrophyanddilatation,interstitialandperiglomerular fibrosis,andinterstitialfocioflymphocytesandplas- macells(Figs.5,6).Trichromestainhighlightedbothth emedullaryamyloidandh eorticalibrosis,butthe tw o were easily distinguishedin Congo red-stained

    sections.Dila tedandatrophiedtubules frequently con-tainedeosinophihchyaline casts(Figs.5,6).Th e glo-meruhwereusuallynormalbylightmicroscopy(Fig.6),ncludingperiodiccid-SchifF(PAS)-s ta inedec- t ions,butsome gazel leshadafe wscleroticglomeruli .Kidneysfromsevengazel leswithrepresenta tive le -sions(Table 2) were examinedby e lec tron microscopy.Amyloidwashmitedtoth emedul laina llseven.n o ne gazel le( 87 -3 6 )focalfusionofepi the l ia lfoo tpro- cesseswasseen,butmostfoo tprocesseswere slender. Electron-denseesangialepos i tscompatiblewith immune complexeswere seenoccasionally infivekid- neys.nw oe l a t edanimals(87-36andherfemale offspring, 4 -386 )there w assphttingandsplintering ofthelaminadensaofth eglomeru larcapil larybase-mentembranes ,hichesembledh easementmembranechangesofAlport'ssyndrome inman.'"Ina llcasesth e mostsevereamyloiddepositiono c- curredinth erenalmedul lae(Table) .Th epresence ofinterstitialfibrosis,andtubulardilatationanda tro-ph ycorre la tedsignificantlywith RM A(Table2).No

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    Fig.5.enalcorticomeduUaryarea,advancedmedullaryamyloidosis.Widespreadtubularatrophy;remainingtubulesar edilatedandcontainhyalinecasts.HE.Fig.6.enalcortex,gazellewithadvancedmedullaryamyloidosis.Glomeruli are juxtaposeddue to loss o f interveningtubules.Surroundingtubulesare dilatedandcontainhyalinecasts.HE.significantcorrelationwasfoundbe tweenRM Aandage,inflammation,o rtubularcasts.Examinationofavailablepedigreeinformationre -vea lednoevidence ofahereditarybasisfo rRM Ain Dorcas azel les .Th enl yunderlyingdiseasewhich occurredwith anyregulari tyin th e Dorcasgazel le pop- ulationasawho l ewasinfectionby Actinomyces(for-merlyCorynebacterium)pyogenes,whichtendedto be chronicorrecurring.Duringth estudyperiodanan- temortemorpost-mortemdiagnosisofA.pyogenesinfectionwasmade in1gazel les ;nine ofwhichwere foundtohaveRM Aa tbiopsyornecropsy(Table) .

    DiscussionTh e patternofrenalamyloidin these gazel lesisun-usualnthatdepositionw asmostprominentinth e medul lae ,withparingofglomerul iandittleorno involvementofcorticalinterstitium.Rena lmedullary amyloidosis (RMA)also frequentlyle dto renalfailure

    anddeathandh ada high prevalence ra te a tnecropsy,making RM A thecurrentleading cause ofdeathamongDorcasgazel les atth e NationalZoologica lPark (NZP) .

    Incontrast,RM Aincatt lefrequentlyoccursincon- junctionwithglomeru laramyloidosis,andifth e glo-merularcomponentismild,itisusuallyasubclinical disease . ' "Althoughherea renopublishednecropsyprevalence ra tesfo rca t t l e ,in o ne largeabattoir surveyRM Awasdiagnosedin only2 .7% of1,326beefcatt le and2 .6% of378dairy cat t le . ' ' In addition,RM A occursindependentlyof age in Dorcasgazel les,but isconsid-e r edanage- re la t edchange incattle.**Th e kidneyappearedto be theprimarysiteof amy- loiddepositionnhistudy,incehemostevere amyloid depositiona lwaysoccurred in th e kidney,andin7/14 casesamyloid w aslimitedtothekidney.More -over,nocasesofamyloidosiswithoutrenalinvolve-mentwere identified inDorcasgazel les .Gross changessimilartothose seeninhesegazel leshavebeenre -portedin otherspecieswithRMA,^''*butthese find- ingsa re obviouslynotspecific.Th e mechanismby whichRM Aimpairsrenalfunc-tion in th e gazel le probablyinvolvesobstructionatth e l eve lofth emedullaryubulesandollectingducts,leading to atrophyandeventuallossofnephrons,with

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    Gaze l l eAmyloidosis 13 3 Table1. Summaryofpathologydata.

    Case* Ag e Se x AmyloidOrganDistribution Cause ofD ea th A.pyogenesInfectionSite 87-595 9yr

    5mo M Kidney,liver Renalfailure Flank87-36 2yr

    11mo F Kidneyonly Euthanasia,renalfailure Submandibular86-571 8yr

    11mo F Kidneyonly Pneumonia Lung86-161 8yr

    5mo M Kidney,liver,pleen,adrenal,rumen,e so phagus Renalfailure Urine,oot,*tendon*86-50 3yr F Kidney,liver,abomasum Euthanasia,renalfailure None9mo85-567 10yr F Kidney,spleen Renalfailure None85-94 5yr10mo

    M Kidney,liver,spleen Euthanasia,renalfailure None85-41 2yr6mo F Kidney,spleen Bacteremia Mandible84-386 9yr F Kidney,heart,abomasum Renalfailure Mandible

    4mo84-148 6yr10mo

    F Kidneyonly Renalfailure None83-611 lyr

    7mo3yr

    F Kidney,spleen,adrenal Tetanus None82-102 M Kidneyonly Inanitionduetomandibular Mandible

    8mo abscess81-740 6yr F Kidneyonly Spiralcolonimpaction None81-674 4yr

    9mo F Kidneyonly Spiralcolonimpaction None81-623 llyr F Kidney,liver,pleen Lungabscess Mandible78-356 13 yr F Kidneyonly Euthanasia,perinealhernias Mandible76-01 5yr

    6moM Kidneyonly Maladaptation None

    =notconfirmedbyculture.

    progressive interstitialfibrosisin th e medul laandcor-t ex .Th etrongcorrelationbe tweenmedullaryamy- loid,ubularatrophyanddilatation,andnterstitialfibrosissupportthisview and make it unlikely thatth e corticalchangesrepresentsuperimposed tubulo-inter-stitialnephritis.Similarcorticallesionsa re seenwith RM Anotherpecies,andimilarmechanisms re thoughttobe responsible fo rth e changes.''*''"

    InadvancedcasesofRMA,tubulardilatationwith castormationesembledth eena l"thyroidization"frequentlye e nit hhronicpyelonephritisnu-mans.*"Th ecorrelationbe tweenRM Aandtubularcastsw as notsignificant. Urinalysis data(primarily o nsamplesco l lec tedfromholdingcagefloors)wasavail-able fo rsix animals,includingtw o (87-595 and87 -3 6 )thathadmarkedubularastormationda tanotshown) .Only o ne animal( 87 - 595 )wasproteinuric(30-100 mg/dlrange by th e reagent stripmethod;Multistix,Am esDivision,MilesLaboratories,Inc.,Elkhart ,IN),

    butthisfindingisofquestionableignificance,ince allamplesro mhisanimalwere eavilycontami-natedbyfeca lmater ia l .Th elackofpronouncedpro- teinuriawoulduggesthatmos tubulesontainingcastsareobstructeddistaltoth easts.Similarly,nchronic pyelonephritis, th e cast-containing tubuleshave beenshowntorepresentseques teredsegmentsoftu-bulesthathave beenpinchedofl'byth e inflammatoryprocess."Infiveof sevenkidneysexaminedbye lec t ronm i- croscopy,occasionalmesangialimmunecomplexde -positswereseen.Thesemayhavebeenre la tedtoA.pyogenesabscesses,sincethree ofth efivehadrecenthistoriesof infection.Splittingandsphnteringofth e glomeru larbasementmembranewasseenultrastruc-turallynwoe l a t ed azel les ,whichesembledh e basementchangesofAlport'ssyndrome inman.'"Rena lpapil larynecrosisisacommonfindingwith RM Ainotherspecies^-'*'^andw asseeninthreeof

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    13 4 Rideoute tal .Table2. Ratingsandrankcorrelationofmedullaryamyloid,cortical changes,andag e .

    Case# MedullaryAmyloid TubularAtrophyand Dilatation InterstitialFibrosis InterstitialInflammation TubularCasts Ag eRank Rating* Rankt Rating Rank Rating Rank Rating Rank Rating Rank

    87-595* 3 + 1 3-H 1 2+ 2 2+ 3 3-H 1 4 84-386* 3 + 2 3-H 2 2 + 4 3 + 1 3 + 2 586-50* 3 + 3 3-H 3 2 + 6 1 + 9 1 + 11 13 84-148 3 + 4 1 + 11 2+ 5 0 2+ 6 8 87-36* 3 + 5 2+ 5 2 + 3 2 + 2 2 + 4 15 86-161 3 + 6 3 + 4 2 + 1 0 3 + 3 785-94 3 + 7 2 + 7 1 + 9 0 1 + 10 1085-567 2+ 8 1 + 14 1 + 10 0 1 + 14 381-740* 2+ 9 2+ 6 1 + 15 1 + 5 1 + 8 9 76-01 2 + 10 1 + 9 1 + 12 0 1 + 12 11 81-623* 2+ 11 1 + 10 1 + 1 1 1 + 8 2+ 5 2 85-41 2+ 12 0 2+ 7 0 0 16 86-571 2+ 13 2+ 8 2+ 8 1+ 6 2+ 7 6 82-102 1 + 14 0 1 + 13 \+ 7 0 14 81-674 1 + 15 \+ 12 1 + 14 \+ 11 1 + 13 12 78-356* \+ 16 1 + 13 1 + 16 2+ 4 1 + 9 1 83-611 1 + 17 0 0 1 + 10 1 + 15 17Correlationcoefficient 0.63 0.60 0.42 0.37 0.38

    * Ratingsreflectlesionseveritybasedo nasubjectivescale of0to 3 + :0=none (excludedfromranking); - :modera t e ;3+=marked.tRankingsare indecreasingorderofseverityo rage.*=examinede lec tronmicroscopically. =statisticallysignificantcorrelation{P

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    Gazel le Amyloidosis 13 5 regulari tyw asachronicorrecurringinfectionby Ac- tinomycesCorynebacterium)yogenes,hichasidentifiedin1 1 animalsduringth e study period.^'Te nof these1 1 were eventua l lynecropsied,andnine ( 82%)were foundtohave R M A .One ofth e1 1isstilllivingandh a snormalerumchemis tr iesbuth asnotbeenbiopsied.Mandibularandubmandibularnfectionswerethemostcommon,affecting5/11nimals.Th e strikingcontrastinth e A.pyogenesinfectionra tesfo rth eamyloidaffectedvs.amyloidunaffectedanimalssuggeststhatthisorganism m ay be an importantfac torinth epathogenesisofRM A inDorcasgazel lesatth e NZP.

    Acknowledgements Drs.RideoutandWallaceweresupportedbyfellowships

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    RequestreprintsfromDr.RichardJ.Montali,DepartmentofPathology,NationalZoologicalPark,Washington,DC20008(USA).